The nation?s grim opioid crisis surges on, with the fentanyls (high potency synthetic opioids) driving unprecedented mortality rates. Drug overdose deaths are now the leading cause of death in those under age 50, with more than 47,000 Americans dying of opioid overdose in 2017. As of December 2018, Philadelphia had the third highest rate of opioid overdose deaths in the country (out-ranked only by Pittsburgh and Baltimore). Fentanyl is present in 84% of the fatal opioid overdoses in Philadelphia. Medication-assisted treatment (MAT) for opioid use disorders ? whether full opioid agonist (methadone), partial opioid agonist (buprenorphine), or a full antagonist (naltrexone) ? is critical for reducing opioid use, and for preventing overdose deaths. Unfortunately, compliance with these life-saving medications is often poor, with ancillary use of non-opioid drugs (especially cocaine) as a common culprit. Cocaine is found in almost half of the opioid overdose deaths in Philadelphia. Identifying promising adjunctive medications that reduce cocaine and other illicit drug use during MAT could improve adherence and save thousands of lives each year. Further, measuring how these medications ?engage? the intended brain targets will speed rational medication development. Toward both these goals, we will cohere significant local addiction resources and research strengths (e.g., in clinical trials and human neuroimaging) to establish a Clinical Laboratory with Integrated Neuroscience (CLIN) for Evaluation of Medications for Substance Use Disorders at the University of Pennsylvania Center for Studies of Addiction. The initial 2-year demonstration project in the UG1 will test the promise of cariprazine, a candidate anti-relapse medication with high D3-affinity, both for preliminary clinical efficacy (reduced illicit drug use, and improved adherence to life-saving naltrexone), and for target engagement (e.g., blunting of drug cue-triggered limbic activation) in patients with opioid use disorders. The project will recruit detoxified opioid patients (up to n=75) within a proximal network of 10 clinical treatment sites. Eligible patients will be randomly-assigned (2:1 ratio) to cariprazine (Vraylar, 1.5 mg daily) vs. placebo, and all will receive up to 3 monthly injections of extended release injectable naltrexone (Vivitrol, 380 mg) in a 12 week outpatient trial (Early Efficacy). A subgroup of imaging- eligible patients will also receive inpatient Target Engagement measures (brain imaging probes for reward and inhibition) prior to beginning the outpatient trial. We will also examine (Exploratory Aim) the impact of hypothesis- driven genetic polymorphisms (e.g., rs6280 for DA D3 receptor) on both the brain and clinical response to the D3 medication. Summary: The highly experienced CLIN team, innovative brain tools, and the novel testing of a D3 medication to improve adherence to naltrexone, are clear strengths of the initial demonstration project, and increase the likelihood that it will both provide new knowledge and save lives. Out- years CLIN strengths include the promise of new candidate medications (e.g., GABA B PAMs, orexin antagonists, cannabidiol) and new, highly-selective PET tracers for measuring opioid receptors and medication occupancy.